EPS8L3 mediates YAP nuclear translocation and promotes liver tumorigenesis
Project/Area Number |
21K15401
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Research Category |
Grant-in-Aid for Early-Career Scientists
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Allocation Type | Multi-year Fund |
Review Section |
Basic Section 49020:Human pathology-related
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Research Institution | Kagoshima University (2022) Hiroshima University (2021) |
Principal Investigator |
NGUYEN THAO 鹿児島大学, 医歯学域歯学系, 助教 (40733837)
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Project Period (FY) |
2021-04-01 – 2024-03-31
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Project Status |
Granted (Fiscal Year 2022)
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Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
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Keywords | EPS8L3 / YAP / HCC / hepatocellular carcinoma / SH3 domain / Hepatocellularcarcinoma / Liver cancer / Carcinogenesis |
Outline of Research at the Start |
Transcriptional regulator Yes-associated protein (YAP) is activated in multiple human cancers and plays critical roles in the tumor initiation, progression, metastasis, and drug resistance. Recently, we demonstrated critical role of EPS8L3 (epidermal growth factor receptor kinase substrate 8-like protein 3) in cholangiocarcinoma (CCA), a deadly form of liver cancer. In this application, we will uncover EPS8L3 as a novel oncogenic factor in CCA that maintains YAP stability and promotes YAP nuclear translocation through physical interaction in vitro and in vivo.
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Outline of Annual Research Achievements |
EPS8L3 physically interacted with YAP, which induces the transcriptional activity of YAP through cytoplasmic sequestration and proteasomal degradation. EPS8L3 kinase activity was essential for protecting YAP from ubiquitin-mediated degradation and cytoplasmic retention. Downregulating EPS8L3 expression inhibited the survival of YAP-activated cancer cell lines and mouse xenograft models. EPS8L3 upregulation was associated with high levels of YAP expression and poor prognosis in clinical tumor samples, confirming its important role for YAP activity in human HCC. These results uncover EPS8L3 as a novel factor that regulates YAP stability and that targeting the YAP degradation pathway controlled by EPS8L3 is a potential strategy for suppressing YAP activity in cancer.
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Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
We completed in vitro and in vivo model and obtained significant results as we expected. Additionally, we extended our research model to other types of cancer. We reported our data in 81st annual meeting of Japanese Cancer Association and 112th annual meeting of the Japanese Society of Pathology and prepared the draft of our manscript.
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Strategy for Future Research Activity |
We will try to complete all necessary experiements and data about the roles of EPS8L3 in hepatocellular carcinoma to have a publication. We are generating the specific peptide to prohibit the interaction between EPS8L3 and YAP, then examine its effects on malignant behaviors of HCC. Additionally, we will collaborate and continue our discovery about the interactions between EPS8L3 and YAP in oral cancer.
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Report
(2 results)
Research Products
(7 results)